Porcine circovirus type 2 (PCV-2) has been identified as the causal agent of postweaning multisystemic wasting syndrome and has been associated with several other disease syndromes in pigs. To date, however, little is known regarding the mechanism(s) underlying the pathogenesis of PCV-2-induced diseases and the interaction of the virus with the host immune system. In the present study, oligodeoxynucleotides (ODNs), with central CpG motifs selected from the genome of PCV-2, were demonstrated to modulate the immune response of porcine PBMCs. Four of the five ODNs tested were demonstrated to act in a stimulatory manner via induction of IFN-alpha production, whereas only one of the five ODNs showed inhibitory activity. Also, this inhibitory ODN was demonstrated to completely inhibit IFN-alpha production induced by the other stimulatory ODNs and showed a variable degree of inhibitory action on other known inducers of IFN-alpha. Although no single common characteristic among resistant or susceptible inducers could be identified, the presence of immune modulatory sequences in the genome of PCV-2 may represent an underlying mechanism of the pathogenesis of PCV-2-associated diseases.